202155orig1s000 - food and drug administration · 2013-02-13 · memorandum department of health...

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

202155Orig1s000

CHEMISTRY REVIEW(S)

ONDQA Division Director’s Memo NDA 202570, ELIQUIS (Apixaban) Tablets, 2.5 and 5.0 mg Date: 22-JUN-2012 The NDA for ELIQUIS (Apixaban) film coated tablets (Bristol Myers Squibb) was submitted via a 501(b)(1) NDA application (standard review clock). All consults to this review have been completed. The drug substance is adequately characterized and controlled; including Ames positive starting materials, impurities, and one intermediate. The drug product immediate release, film coated tablets (2.5 mg [yellow debossed with “893’] and 5.0 mg [pink debossed with “894”]) are packaged for commercial distribution in HDPE bottles of 60 or 180 count as well as a 14 count blister package (5.0 mg) for physician samples. An expiry period of 36 months for the commercial packages when stored at USP controlled room temperature is approved. For the finished tablets in the bulk container, and expiry of 12 months at ICH intermediate condition is also approved. This NDA is recommended for approval from a Chemistry, Manufacturing and Controls standpoint. Respecfully submitted, Richard (Rik) Lostritto, Acting Deputy Office Director, ONDQA

Reference ID: 3149696

---------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically and this page is the manifestation of the electronicsignature.---------------------------------------------------------------------------------------------------------/s/----------------------------------------------------

RICHARD T LOSTRITTO06/22/2012


MEMORANDUM DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH DATE: May 18, 2012 TO: File THROUGH: Ramesh K. Sood, Ph.D., Branch Chief, ONDQA

FROM: Charles F. Jewell Jr, Ph.D., Sr. Regulatory Review Chemist, ONDQA SUBJECT: Final Chemistry, Manufacturing and Controls (CMC) Approval Recommendation for NDA 202-155 (Apixaban) On 28 February 2012 the CMC review for the NDA 202-155 (Apixaban) was filed indicating the adequacy of the application from the CMC perspective, pending a decision from the Office of Compliance on GMP inspection results of the establishments involved in the manufacturing process of apixaban drug substance and drug product. This memo is to confirm the overall acceptable rating based on the GMP inspection results of all the pertinent sites, see the detailed report below. This confirms that NDA 202-155 (Apixaban) is approved from the CMC perspective.

Final Establishment Evaluation Report



CHARLES F JEWELL05/18/2012

RAMESH K SOOD05/18/2012


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DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service

Food and Drug Administration Center for Drug Evaluation and Research

METHODS VALIDATION REPORT SUMMARY

TO: Charles Jewell and William Adams, CMC Reviewer

Office of New Drug Quality Assessment (ONDQA) E-mail Address: [email protected]; [email protected] Phone: (301)-796-4232 and (301)-796-1321 Fax: (301)-796-9747

FROM: FDA Division of Pharmaceutical Analysis

James Allgire, Team Leader Suite 1002

1114 Market Street St. Louis, MO 63101 Phone: (314) 539-3813 Through: Benjamin J. Westenberger, Deputy Director Phone: (314) 539-3869 SUBJECT: Methods Validation Report Summary

Application Number: NDA 202155 Name of Product: Eliquis (apixaban) Tablets, 2.5 mg and 5 mg

Applicant: Bristol-Myers Squibb Company

Applicant’s Contact Person: Porter P. Layne, group Director, GRS

Address: P.O. Box 4000, Princeton, NJ 08543-4000 Telephone: 609-252-4722 Fax: 609-252-6000 Date Methods Validation Consult Request Form Received by DPA: 12/08/11

Date Methods Validation Package Received by DPA: 12/08/11

Date Samples Received by DPA: 12/23/11

Date Analytical Completed by DPA: 03/12/12

Laboratory Classification: 1. Methods are acceptable for control and regulatory purposes. 2. Methods are acceptable with modifications (as stated in accompanying report). 3. Methods are unacceptable for regulatory purposes. Comments: Cover memo and summary of results are attached.


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Center for Drug Evaluation and Research Division of Pharmaceutical Analysis St. Louis, MO 63101 Tel. (314) 539-3815

Date: March 12, 2012 To: Charles Jewell, Review Chemist (HFD-800) William Adams, Review Chemist (HFD-800) Through: B. J. Westenberger, Deputy Director, Division of Pharmaceutical Analysis, (HFD-920) From: Michael Trehy, Chemist (HFD-920) Subject: Method Validation for NDA 202155 Eliquis® Apixaban 2.5 mg tablets

The following methods were evaluated and are acceptable for quality control and regulatory purposes:

• 95011145 Apixaban Tablets – Identification, Potency and Content Uniformity (HPLC) and method

• 95011189 Apixaban Tablets – Potency, Impurities/Degradants, Identification (HPLC)

The Division of Pharmaceutical Analysis (DPA) has the following comment pertaining to this method. A typographical error on page 9 of method 95011145 was found.

DEPARTMENT OF HEALTH & HUMAN SERVICES Food and Drug Administration


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Summary of Results NDA 202155

Method: 95011145 Apixaban Tablets – Identification, Potency and Content Uniformity (HPLC) Identity: relative retention time of sample to standard Potency: % limit % Content uniformity % label claim: % acceptance value Method: 95011189 Apixaban Tablets – Potency, Impurities/Degradants, Identification (HPLC) Identity: relative retention time of sample to standard Potency: limit % % Impurities: prep-1 prep-2 avg(2) Limit


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JAMES F ALLGIRE03/13/2012

BENJAMIN J WESTENBERGER03/15/2012




YONG WANG02/27/2012

WILLIAM M ADAMS02/28/2012





YONG WANG02/15/2012




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DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service

Food and Drug Administration Center for Drug Evaluation and Research

METHODS VALIDATION CONSULT REQUEST FORM

TO: FDA Division of Pharmaceutical Analysis

Attn: Benjamin (Nick) Westenberger Suite 1002

1114 Market Street St. Louis, MO 63101

FROM: Charles Jewell and William Adams, CMC Reviewer

Kasturi Srinivasachar, CMC Lead Office of New Drug Quality Assessment (ONDQA) E-mail Address: [email protected]; [email protected] Phone: (301)-796 4232 and (301)-796 1321 Fax.: (301)-796 9747

Through: Ramesh Sood Phone: (301)-796 1466 and Jeannie David, ONDQA Methods Validation Project Manager Phone: 301-796-4247 SUBJECT: Methods Validation Request

Application Number: NDA 202155 Name of Product: Eliquis (apixaban) Tablets, 2.5 mg and 5 mg

Applicant: Bristol- Myers Squibb Company

Applicant’s Contact Person: Porter P. Layne, Group Director, GRS

Address: P.O. Box 4000, Princeton, NJ 08543-4000 Telephone: 609-252 4722 Fax: 609-252 6000 Date NDA Received by CDER: 9/28/2011 Submission Classification/Chemical Class: NME

Date of Amendment(s) containing the MVP: 9/28/2011 Special Handling Required: No

DATE of Request: December 1, 2011 DEA Class: N/A

Requested Completion Date: 1/20/2012 Format of Methods Validation Package (MVP)

PDUFA User Fee Goal Date: 3/28/2012 Paper Electronic Mixed

We request suitability evaluation of the proposed manufacturing controls/analytical methods as described in the subject application. Please submit a letter to the applicant requesting the samples identified in the attached Methods Validation Request. Upon receipt of the samples, perform the tests indicated in Item 3 of the attached Methods Validation Request as described in the NDA. We request your report to be submitted in DARRTS promptly upon completion, but no later than 45 days from date of receipt of the required samples, laboratory safety information, equipment, components, etc. We request that you notify the ONDQA Methods Validation Requestor and the ONDQA Methods Validation Project Manager of the date that the validation process begins. If the requested completion date cannot be met, please promptly notify the ONDQA Methods Validation Requestor and the ONDQA Methods Validation Project Manager. Upon completion of the requested evaluation, please assemble the necessary documentation (i.e., original work sheets, spectra, graphs, curves, calculations, conclusions, and accompanying Methods Validation Report Summary). The Methods Validation Report Summary should include a statement of your conclusions as to the suitability of the proposed methodology for control and regulatory purposes and be electronically signed by the laboratory director or by someone designated by the director via DARRTS. The ONDQA CMC Reviewer, ONDQA Methods Validation Project Manager, and ONDQA CMC Lead/Branch Chief should be included as cc: recipients for this document. All information relative to this application is to be held confidential as required by 21 CFR 314.430.


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Additional Comments:

Methods Validation Request Criteria

MV Request Category

Description

0 New Molecular Entity (NME) application, New Dosage Form or New Delivery System

1 Methods using new analytical technologies for pharmaceuticals which are not fully developed and/or accepted or in which the FDA laboratories lack adequate validation experience (e.g., NIR, Raman, imaging methods)

2

Critical analytical methods for certain drug delivery systems (e.g., liposomal and microemulsion parenteral drug products, transdermal and implanted drug products, aerosol, nasal, and dry powder inhalation systems, modified release oral dosage formulations with novel release mechanisms)

3 Methods for biological and biochemical attributes (e.g., peptide mapping, enzyme-based assay, bioassay)

4 Certain methods for physical attributes critical to the performance of a drug (e.g., particle size distribution for drug substance and/or drug product)

5 Novel or complex chromatographic methods (e.g., specialized columns/stationary phases, new detectors/instrument set-up, fingerprinting method(s) for a complex drug substance, uncommon chromatographic method


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6 Methods for which there are concerns with their adequacy (e.g., capability of resolving closely eluting peaks, limits of detection and/or quantitation)

7 Methods that are subject to a “for cause” reason



KASTURI SRINIVASACHAR12/01/2011


JEANNIE C DAVID12/08/2011ONDQA Methods Validation Project Manager


DATE: November 30, 2011 TO: Extended Apixaban (NDA 202-155) Review Team FROM: William (Mike) Adams ([email protected]; 301-796-1321 THROUGH: Ramesh Sood, Ph.D., Branch Chief SUBJECT: CMC (Chemistry, Manufacturing & Controls) Product Quality Manufacturing

Memo for Drug Product for the upcoming Pre-Approval Inspection. The proposed drug product is an oral film-coated tablet in two strengths, 2.5mg and 5.0mg, which are packaged in HDPE bottles and clear blister packs. Tablets are stated to be manufactured and controlled at the BMS sites at Humacao, P.R. and Mount Vernon, IL. Packaging is stated to be performed at the BMS sites at Mount Vernon, IL for blisters and bottles, and at Agnani, Italy for blisters. The packaging system for transfer of bulk tablets between sites has not been described in detail and the controls for release and acceptance at each site are being requested. The application includes for tablet formulation and in-process material attributes. Both are addressed in the product development discussion which is under review.

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Contact Information • Drug Substance: Charles Jewel (([email protected]; 301-796-4232) • Drug Product: William (Mike) Adams ([email protected]; 301-796-1321 • Biopharmaceutics: Saundra Suarez ([email protected]; 301-796-2158) • Methods and Testing: Yong Wang ([email protected]; 301-796-1139) • Project Manager, Quality: Don Henry ([email protected]; 301-796-4227) • CMC Lead: Kasturi Srinivasachar ([email protected]; 301-796-1760) • Branch Chief: Ramesh Sood ([email protected]; 301-796-1466)

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DATE: November 07, 2011 TO: Extended Apixaban (NDA 202-155) Review Team FROM: Charles Jewell, Ph.D. 301-796-4232, [email protected], Reviewer of Drug

Substance Section THROUGH: Ramesh Sood, Ph.D., Branch Chief SUBJECT: CMC (Chemistry, Manufacturing & Controls) Product Quality Manufacturing

Memo for Drug Substance for the upcoming Pre-Approval Inspection. Swords Laboratories, Watery Lane, Swords, County Dublin, Ireland has been proposed as the main manufacturing site for Apixaban drug substance for use in NDA 202155. This site is a facility of Bristol-Myers Squibb, the applicant for the subject NDA. This site has direct responsibility for the following: • Quality control testing and release of • Manufacture, quality control testing and release of • Manufacture, quality control testing and release of apixaban

, provided to this site by two external vendors who have contracts with the applicant to provide this material. has been designed as an important step in ensuring the quality of apixaban drug substance.

Synopsis of the Manufacturing Process


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Initial Quality Assessment Branch I

OND Division: Division of Cardiovascular and Renal Products NDA: 202155

Applicant: Bristol Myers Squibb and Pfizer Letter Date: 3 Nov 2010 Stamp Date: 3 Nov 2010 PDUFA Date: TBD Tradename: None proposed at this time Established Name: Apixaban Dosage Form: Tablets, 2.5 mg and 5 mg Route of Administration: Oral Indication: Prevention of stroke or systemic embolism associated

with atrial fibrillation Assessed by: Kasturi Srinivasachar ONDQA Fileability: Yes



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KASTURI SRINIVASACHAR01/06/2011



PRODUCT QUALITY (Small Molecule) FILING REVIEW FOR NDA or Supplement (ONDQA)

File name: 090513-Product Quality Filing Review.doc Page 2 Version Date: 05132009

7.

Are drug substance manufacturing sites identified on FDA Form 356h or associated continuation sheet? For each site, does the application list: • Name of facility, • Full address of facility including

street, city, state, country • FEI number for facility (if

previously registered with FDA) • Full name and title, telephone, fax

number and email for on-site contact person.

• Is the manufacturing responsibility and function identified for each facility?, and

• DMF number (if applicable)

X

8.

Are drug product manufacturing sites are identified on FDA Form 356h or associated continuation sheet. For each site, does the application list: • Name of facility, • Full address of facility including

street, city, state, country • FEI number for facility (if

previously registered with FDA) • Full name and title, telephone, fax

number and email for on-site contact person.

• Is the manufacturing responsibility and function identified for each facility?, and

• DMF number (if applicable)

X





SANDRA SUAREZ11/06/2011

YONG WANG11/07/2011



202155orig1s000 - food and drug administration · 2013-02-13 · memorandum department of health...

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